OVERALL PROJECT SUMMARY ? CORNELL ME/CFS COLLABORATIVE RESEARCH CENTER Despite the fact that an estimated 1 million people or more in the U.S. suffer from Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), remarkably little is known about the etiology of the disease and effective therapies are lacking. ME/CFS is characterized by debilitating fatigue that is not ameliorated by rest or due to any other medical condition, and a myriad of symptoms, including musculoskeletal pain, headaches, cognitive difficulties orthostatic intolerance, and sleep disturbances. There are no simple scientifically validated tests for the illness, leading to a great deal of uncertainty among clinicians when evaluating patients who report prolonged and unexplained fatigue. Fatigue and other symptoms are exacerbated following exertion beyond a patient's particular threshold, a hallmark symptom of ME/CFS known as post-exertional malaise (PEM). The absence of biomarkers for the disease and the lack of available research models for ME/CFS amplify the deficiency of research data produced in the field to date. Recent studies implicate immune dysregulation and neuroinflammation in ME/CFS. By leveraging the experience, capabilities and varied backgrounds of researchers from four different institutions (Cornell Ithaca, Weill Cornell Medicine, Ithaca College, and Boyce Thompson Institute), as well as key personnel from many other organizations, the proposed Cornell ME/CFS Collaborative Research Center will apply neuroimaging, proteomics, metabolomics, and single cell RNA and microRNA sequencing approaches to interrogate the underlying biomedical mechanisms that contribute ME/CFS, by thorough examination of biomarkers from patients and controls both before and after symptom provocation through exercise. Three research projects will seek to (1) examine oxidative stress in the brain and neuroinflammation (Project 1), (2) examine inflammatory molecules, metabolism, and cargo of extracellular vesicle (Project 2) and (3) determine levels of gene dysregulation across the immune system (Project 3). These three research projects are supported by two cores; one Clinical Core (Core 1: Cornell CRC Clinical Core), which will recruit and screen patients/controls and oversee cardiopulmonary exercise testing and a Research Core (Core 2: Integrative Data Analysis Core), which will support CRC members with data management and bioinformatics analyses, while assimilating data across the project components to provide an integrated view of the assayed characteristics about ME/CFS subjects studied by the Center. All Center activities will be coordinated through an Administrative Core, which will foster synergy and integration within the Center, while also being the platform for collaboration with other Collaborative Research Centers and the Data Management Coordinating Center. The Administrative Core will also be responsible for outreach activities, designed to increase awareness and understanding of ME/CFS within the research community, health professionals, and the general public.